The present invention relates to compositions comprising huperzine compounds and nicotinic compounds and to methods of using huperzine compounds and nicotinic compounds in combination to provide a neuroprotective effect.
Neuronal dysfunction includes cognitive decline, which is characterized by concentration loss, memory-acquisition loss, and information-storage or retrieval loss. Neuronal dysfunction can also result from central nervous system (xe2x80x9cCNSxe2x80x9d) injury, such as stroke, spinal-cord injury, and peripheral-nerve injury. Cognitive decline is symptomatic of neuronal disorders, such as cognitive decline associated with aging and minimal cognitive impairment (also known as minimal cognitive disorder) as well as severe neurodegenerative disorders, such as Alzheimer""s disease. Neuronal dysfunction is also associated with disorders that result in loss of motor skills, such as Parkinson""s disease and amyotrophic lateral sclerosis. It is thought that degeneration of the central cholinergic system contributes to cognitive decline.
For example, there is much evidence indicating that the memory and attention deficits in patients with Alzheimer""s disease are due to degeneration of cholinergic systems that originate in the basal-forebrain-cholinergic system and innervate the neocortex, hippocampus and other brain areas (Coyle et al., 1983, Science 219:1184.) Additional evidence suggests that nicotinic acetylcholine receptors (xe2x80x9cnAChRxe2x80x9d) play a role in cholinergic dysfunction, and nicotine and its analogs can affect these dysfunctions. Nicotine activates nAChR, eliciting a number of functional responses, including neurotransmitter release and neurogenic control of cerebral blood flow (S. P. Arneric and M. Williams, 1994, Recent Advances In the Treatment of Neurodegenerative Disorders and Cognitive Function p 58; Linville et al., 1993, J. Pharmacol. Exp. Ther. 267:440).
Nicotine improves information processing and attention in patients with Alzheimer""s type dementia, as well as the performance of cognitively demanding tasks in healthy human adult subjects (Sahakian et al., 1989, Br. J. Psychiatry 154:797; Wesnes et al., 1984, Psychopharmacology 82:147). Nicotine has also been shown to improve learning and memory performance and to reverse deficits in models of impaired-cognitive performance (Decker, 1992, Brain Res. 572:281). In animal models of cholinergic disturbance produced by NBM lesions, chronic pretreatment with nicotine reduced cell loss in the neocortex (Sjak-Shie et al., 1991, in Cholinergic Basis for Alzheimer Therapy, pp. 379). Analogs of nicotine can similarly exhibit neuroprotective and cognitive-enhancing properties (Sullivan et al., 1995, Proc. West. Pharmacol. Soc. 38:127; Arneric et al., 1994, J. Pharmacol. Exp. Ther. 270:310; Decker et al., 1994, J. Pharmacol. Exp. Ther. 270:318).
Cortical neurodegeneration in some neuropathies (e.g., stroke, ischemia, etc.) has been attributed to glutamate binding to N-methyl-D-aspartate (xe2x80x9cNMDAxe2x80x9d) receptors, which play a crucial role in glutamate-induced neurodegeneration (Mattson, 1988, Brain Res. 13:174; Choi et al., 1989, J. Neurosci. Res. 23:116; Hartley and Choi, 1989, J. Pharmacol. Exp. Ther. 250:752; Meldrum and Garthwaire, 1990, Trends Pharmacol. Sci. 11:379). For example, symptoms of neuronal damage caused by organophosphate (xe2x80x9cOPxe2x80x9d) toxicity (i.e. tremors, seizures or convulsions) have been partially attributed to the release of large quantities of glutamate during OP intoxication. The released glutamate causes activation of NMDA receptors and increases Ca2+ influx that in turn causes persistent elevation in Ca2+ concentrations, eventually resulting in neuronal death (Ved et al., 1997, Neuroreport 8:963; Choi, 1994, Ann. NY Acad. Sci. 747:162). Nicotine protects cultured cortical neurons against NMDA receptor-mediated, glutamate-induced cell death (Marin et al., 1994, Neuropharmacology and Neurotoxicology 5:1977; Kaneko et al, 1997, Brain Research 765:135. Akaike et al., 1994, Prog. Brain Res. 130:391).
Administration of acetylcholinesterase (xe2x80x9cAChExe2x80x9d) inhibitors such as tacrine, donepezil, and others have proven useful in the treatment of Alzheimer""s disease. Two relatively new lycopodium alkaloids, (xe2x88x92)-huperzine A and B, isolated from Huperzia serrata (Thunb.) Trev., a Chinese folk medicine, appear superior to these and other compounds such as tacrine and physostigmine (U.S. Pat. No. 5,177,082 to Yu et al.; Liu et al., 1986, Can. J. Chem. 64:837; Ayer et al., 1989, Can. J. Chem. 67:1077; Ayer et al., 1989, Can. J Chem. 67:1548). The structures of huperzine A and huperzine B are shown in J. Liu et al., Can. J. Chem. 64:837-839 (1986), incorporated herein by reference. The structures of(xe2x88x92)-huperzine A and (xe2x88x92)-huperzine B are depicted below. 
Huperzine has been shown to ameliorate the memory loss associated with Alzheimer""s disease (Kozikowski et al., 1999, Acc. Chem. Res., 32:641). And, like nicotine, huperzine A significantly reduces the neuronal-cell death caused by glutamate. In addition, the neuroprotective effect of huperzine A against glutamate increases with age. Ved et al., 1997, Neuroreport 8:963.
Other clinical and histopathological findings of Alzheimer""s disease include formation of paired helical filaments and amyloid plaques, along with increased formation of amyloid protein. In artificial lipid bilayers, amyloid proteins have been shown to form cation channels that conduct calcium and other ions. The resulting ion fluxes could be homeostatically catastrophic if such channels are expressed in cells, supporting the concept that cell death in Alzheimer""s disease can be partly the result of amyloid channel activity. This theory is supported by the finding that xcex2-amyloid peptide is toxic to neurons. Nicotine protects against this toxicity.
The compounds currently in clinical use for treating or ameliorating neuronal dysfunction have significant side effects. Huperzine has been used for many years as a Chinese herbal remedy for alleviating memory problems (Kozikowski, 1999, Acc. Chem. Res. 32:641; Bai, 1993, Pure Appl. Chem. 65:1103). Nonetheless, there remains a need in the art for additional and more effective therapies that treat, prevent, or reverse neuronal dysfunction, such as cognitive decline characterized by concentration loss; memory-acquisition loss; information-storage or retrieval loss; neuronal disorders such as cognitive decline associated with aging and minimal cognitive impairment; severe neurodegenerative disorders such as Alzheimer""s disease; neuronal dysfunction associated with loss of motor skills, such as Parkinson""s disease and amyotrophic lateral sclerosis; neuronal dysfunction resulting from CNS injury such as stroke, spinal-cord injury, and peripheral-nerve injury. There is a particular need for additional and more effective therapies that treat, prevent, or reverse Alzheimer""s disease and minimal cognitive impairment.
Citation or identification of any reference in Section 2 of this application is not an admission that such reference is prior art to the present invention.
In one embodiment, the present invention provides a composition comprising a huperzine compound or pharmaceutically acceptable salt or hydrate thereof and a nicotinic compound or pharmaceutically acceptable salt or hydrate thereof. The composition can further include a pharmaceutically acceptable carrier, diluent or excipient, and can be administered to an animal subject, including a human, in connection with the methods of the invention to treat, prevent, or reverse neuronal dysfunction. Examples of neuronal dysfunction treated, prevented, or reversed using the compositions of the invention include, but are not limited to, cognitive decline characterized by concentration loss; memory-acquisition loss; information-storage or retrieval loss; neuronal disorders such as cognitive decline associated with aging and minimal cognitive impairment; severe neurodegenerative disorders such as Alzheimer""s disease; and neuronal dysfunction associated with loss of motor skills, such as Parkinson""s disease and amyotrophic lateral sclerosis. The compositions of the invention can also be used to treat, prevent, or reverse neuronal dysfunction resulting from CNS injury such as stroke, spinal-cord injury, and peripheral-nerve injury. The compositions of the invention are particularly useful for treating, preventing, or reversing Alzheimer""s disease and minimal cognitive impairment.
In a separate embodiment, the compositions of the invention are formulated in a patch for transdermal administration.
In another embodiment, the invention comprises a method of providing neuroprotection in a subject, said method comprising adjunctively administering to a subject in need thereof a huperzine compound or a pharmaceutically acceptable salt or hydrate thereof and a nicotinic compound or pharmaceutically acceptable salt or hydrate thereof in amounts effective to provide neuroprotection.
In still another embodiment, the invention relates to a method for treating, preventing, or reversing a neuronal dysfunction, comprising adjunctively administering to a patient in need thereof effective amounts of a huperzine compound, pharmaceutically acceptable salt or hydrate thereof and a nicotinic compound, pharmaceutically acceptable salt or hydrate thereof.
The methods of the invention preferably provide a prophylactic or therapeutic neuroprotective effect. For example, the invention provides methods of treating, preventing, or reversing neuronal dysfunction. Examples of neuronal dysfunction treated, prevented, or reversed using the methods of the invention include, but are not limited to, cognitive decline characterized by concentration loss; memory-acquisition loss; information-storage or retrieval loss; neuronal disorders such as cognitive decline associated with aging and minimal cognitive impairment; severe neurodegenerative disorders such as Alzheimer""s disease; and neuronal dysfunction associated with loss of motor skills such as Parkinson""s disease and amyotrophic lateral sclerosis. The methods of the invention can also be used to treat, prevent, or reverse neuronal dysfunction resulting from CNS injury such as stroke, spinal-cord injury, and peripheral-nerve injury.
In still another embodiment, the invention comprises a method of providing neuroprotection, comprising contacting a neuron with a huperzine compound or pharmaceutically acceptable salt or hydrate thereof and a nicotinic compound or pharmaceutically acceptable salt or hydrate thereof in amounts effective to provide neuroprotection.
The present invention may be understood more fully by reference to the following figures, detailed description and illustrative examples, which are intended to exemplify non-limiting embodiments of the invention.